METTL4, short for methyltransferase-like protein 4, is a key methyltransferase involved in multiple biological processes. It mediates N6-methyladenine (6mA) methylation of mitochondrial DNA (mtDNA) and N6-methyladenosine (m6A) modification of certain RNAs, playing crucial roles in mitochondrial homeostasis, gene expression regulation, and various biological pathways related to diseases [1,2,3,4,5,6,7,8]. Genetic models, such as knockout mouse models, are valuable tools for studying its functions.

In heart failure models, cardiomyocyte-specific deletion of the Mettl4 gene eliminated mtDNA 6mA excess, preserved mitochondrial function, and mitigated HF development [1]. In sepsis-induced acute lung injury, METTL4 knockdown alleviated ferroptosis in alveolar epithelial cells [2]. In atherosclerosis, Mettl4Mac-KO-Apoe-/-mice displayed suppressed mtDNA 6mA levels and atherosclerotic progression [3]. These KO models clearly show that METTL4-mediated modifications are involved in the pathogenesis of these diseases.

In conclusion, METTL4 is essential in regulating mitochondrial function through mtDNA 6mA methylation and influencing processes like ferroptosis. The use of Mettl4 KO/CKO mouse models has significantly contributed to understanding its role in heart failure, acute lung injury, and atherosclerosis, highlighting its potential as a therapeutic target for these diseases.